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METTL14 promotes migration and invasion of choroidal melanoma by targeting RUNX2 mRNA via m6A modification.

ABSTRACT: The modification of N6-methyladenosine is involved in the progression of various cancers. This study aimed to clarify its regulatory mechanism in the pathogenesis of choroidal melanoma. Expression of methyltransferase-like 14 in choroidal melanoma or normal choroidal tissues was determined by Western blot and immunohistochemistry. The impacts of methyltransferase-like 14 on invasion and migration of choroidal melanoma cells were determined using functional and animal experiments. The interaction between methyltransferase-like 14 and its downstream target was identified by methylated RNA immunoprecipitation and a dual-luciferase reporter assay. Additionally, Wnt/β-catenin signalling pathway was evaluated by Western blot. Methyltransferase-like 14 was upregulated in choroidal melanoma compared to the normal choroidal tissues. Overexpression or knockdown of methyltransferase-like 14 enhanced or inhibited the invasion and migration of choroidal melanoma cells, respectively, both in vivo and in vitro. Methyltransferase-like 14 directly targeted downstream runt-related transcription factor 2 mRNA, depending on N6-methyladenosine. Additionally, the Wnt/β-catenin signalling pathway was activated by methyltransferase-like 14 in choroidal melanoma cells. Our study identified a novel RNA regulatory mechanism in which runt-related transcription factor 2 was upregulated by enhanced expression of methyltransferase-like 14 via N6-methyladenosine modification, thus facilitating migration and invasion of choroidal melanoma cells.

SUBMITTER: Zhang X

PROVIDER: S-EPMC9667526 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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METTL14 promotes migration and invasion of choroidal melanoma by targeting RUNX2 mRNA via m6A modification.

Zhang Xi X Zhang Xiaonan X Liu Tengyue T Zhang Zhe Z Piao Chiyuan C Ning Hong H

Journal of cellular and molecular medicine 20221020 22

The modification of N6-methyladenosine is involved in the progression of various cancers. This study aimed to clarify its regulatory mechanism in the pathogenesis of choroidal melanoma. Expression of methyltransferase-like 14 in choroidal melanoma or normal choroidal tissues was determined by Western blot and immunohistochemistry. The impacts of methyltransferase-like 14 on invasion and migration of choroidal melanoma cells were determined using functional and animal experiments. The interaction ...[more]

PMID: 36264762

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Project description:BackgroundHemorrhoids are a frequently-occurring disease of the anorectal system that is often accompanied by vascular hyperplasia and edema. A METTL14-mediated RNA N-6 methyladenosine (m6A) modification can improve mRNA stability and increase its transcriptional and translational activities, closely related to the occurrence of many diseases.MethodsWestern blot, qPCR, and immunofluorescence staining were used to detect the levels of gene and protein expression. Haematoxylin and eosin staining was used for histopathological examination. RNA immunoprecipitation-PCR and RNA dot blotting were used to detect mRNA m6A modification.ResultsObvious signs of angiogenesis (CD31+/vWF+) were identified in the hemorrhoids. High levels of METTL14 expression on vascular endothelial cells (CD31+) suggested that angiogenesis was accompanied by differential modification of m6A RNA. It was subsequently found that the level of miR-4729 expression was significantly decreased in hemorrhoid tissues. The luciferase reporter enzyme assay results suggested that miR-4729 silenced its expression by targeting the 3'UTR of METTL14 mRNA. MiR-4729 overexpression in human umbilical vein endothelial cells (HUVECs) inhibited the proliferation and migration of HUVECs in vitro and vascular structure formation in the outer matrix. MiR-4729 overexpression significantly inhibited endogenous METTL14 expression in HUVECs and reduced the entire m6A RNA modification, especially the level of m6A methylation at the specific site of the 3' UTR of TIE1 mRNA. Moreover, miR-4729 overexpression significantly inhibited the molecular loop of the TIE1/VEGFA signaling pathway in HUVECs.ConclusionsOur findings confirmed that the down-regulation of miR-4729 in hemorrhoid vascular endothelial cells was one of the main reasons for vascular proliferation. The overexpression of miR-4729 in vascular endothelial cells decreased the global mRNA methylation and TIE1 mRNA 3'UTR-specific site methylation by silencing METTL14 expression, reducing TIE1 mRNA stability, down-regulating the TIE1/VEGFA signal molecular loop expression, and weakening angiogenesis ability.

Dataset Information

METTL14 promotes migration and invasion of choroidal melanoma by targeting RUNX2 mRNA via m6A modification.

Publications

METTL14 promotes migration and invasion of choroidal melanoma by targeting RUNX2 mRNA via m6A modification.

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